Summary of Work: A series of projects are ongoing in the cyclooxygenase (COX) knockout mice. 1) Tumorigenesis in the COX1 and COX2 null strains has been studied using the DMBA/TPA two stage skin model. Papilloma formation was reduced by 60% in both of the knockout strains compared to the control. The effects of NSAIDs on tumorigenesis are also being studied and compared to the effects of the knockouts. 2) Air pouchs have been successfully formed on the COX-1 and COX-2 knockout mice. Their responses to inflammatory agents (carageenan and TPA) are being studied. Differences in the responses of the COX-1 and -2 animals have been observed in production of PGE2 and LTB4, and in the cells recruited to the site of inflammation. 3) COX-1 and COX-2 mice are being bred to APC (min) mice which are susceptible to spontaneous adenopolyposis of the colon. The effects of the knockouts on spontaneous colon carcinogenesis will be studied in the absence or presence of NSAIDs. 4) The COX-1 and COX-2 knockouts are being bred into the C57/BL6J and 129J inbred strains. These mice will provide a homogenous genetic background for future studies and should lead to improved statistics in all studies.